Studies from animal models have suggested the possibility that hypothalamic-pituitary-adrenal axis (HPA) and other neuroendocrine dysfunctions may play a role in rheumatoid arthritis (RA) and other autoimmune conditions. For these and other reasons, we are conducting studies investigating neuroendocrine function in patients with RA and related arthropathies. We have completed one study that supports our view that adrenal hormone production is blunted in patients with RA. We investigated circadian secretion of ACTH, cortisol, interleukin-1 (IL-1) and IL-6 and demonstrated that RA patients show "normal" or occasionally low 24-hour cortisol production, while plasma IL-6 levels are markedly elevated. Of interest, we noted that IL-6, like ACTH and cortisol, is secreted with a circadian pattern, and the pulses of cortisol are linked to pulses of IL-6, with IL-6 leading cortisol by about 1 hour. Linkage of IL-6 secretion to ACTH secretion was much weaker. These data suggest that IL-6 may directly stimulate adrenal secretion of cortisol, but, more importantly, the data support our hypothesis that adrenal cortisol production in RA patients is "inappropriately normal" or blunted. We would expect markedly increased cortisol production the setting of high IL-6 levels. Additional data have been collected on adrenal androgen levels in new-onset RA patients. Interestingly, the production of adrenal androgens, such as dehydroepiandrosterone (DHEA) and (DHEA-S), is even more abnormal than cortisol. These data indicate that adrenal hypofunction in RA patients is not restricted to cortisol but suggest more global neuroendocrine dysfunction. Initial studies of HPA axis and sympatho-adrenal function in patients with fibromyalgia were completed. These patients exhibit blunted HPA responses to corticotropin releasing hormone (CRH) and strikingly low levels of neuropeptide Y. These data suggest abnormalities in the two major components of the stress response system may play a role in this perplexing condition. We also completed a study testing the hypothesis that corticosteroids mediate some of their peripheral antiinflammatory effects by stimulating somatostatin, a well-known antiinflammatory peptide. In an animal model of aseptic inflammation, we noted increased local expression of somatostatin following corticosteroid treatment in concert with suppression of local proinflammatory substances such as substance P, CRH and tumor necrosis factor-alpha.